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Interleukin-21 (IL-21) has been reported to possess many functions on immune cells such as T cells, B cells, NK cells and dendritic cells. We found that IL-21 was the 6th member of common gamma chain cytokine family. We are focusing on IL-21-induced signal transduction and its function on immune cells
＜Education and Research Activities＞
1. Molecular mechanisms of regulation of IL-21-induced signal transduction.
We identified some interacting molecules with IL-21 receptor. We are now studying the functional roles of these molecules. Furthermore we are now searching novel molecules involving IL-21-induced signaling.
2. Function of IL-21 on T cells.
We reported that human IL-21 protein was produced from activated central and effector CD4+ memory T cell populations, especially differentiated to Th1 or Th17 cells but not to Th2 cells, by establishing a monoclonal antibody against human IL-21. We also demonstrated that IL-21 produced from these cells supported not only these memory cell but also naive cell proliferation with IL-7 and/or IL-15 in absence of antigen stimulation. These results suggest that produced IL-21 maintains bystander memory and naive CD4+ T cell homeostasis with IL-7 and/or IL-15.
3. Analysis of isoform of IL-21.
We identified an isoform of human and mouse IL-21. These are splicing variant form of originally reported IL-21. We are now preparing the isoform expressing transgenic mice to analyze the function of IL-21 isoform.
4. IL-21 and immune disorders.
Development of autoimmune diseases is very complicated and involves multiple factors. Recently IL-17 producing CD4+ T cells (Th17 cells) are shown to be an important effector cells in autoimmune and inflammatory diseases in mice. Because mouse IL-21 was demonstrated to be a very important factor for Th17 differentiation with TGF-beta and IL-6 in vivo, IL-21 may be a key factor for the development of these diseases. However human factors producing Th17 cells are not well understood, we already reported that differentiated Th17 cells express also IL-21. We are now trying to find out the functional roles of human IL-21 on human Th17 cell differentiation and on these diseases development.
Juliana FM, Nara H, Onoda T, Rahman M, Araki A, Jin L, Fujii H, Tanaka N, Hoshino T and Asao H; Apurinic/apyrimidinic endonuclease1/redox factor-1 (Ape1/Ref-1) is essential for IL-21-induced signal transduction through ERK1/2 pathway. Biochem. Biophys. Res. Commun. 420, 628-634, 2012.
Nara H, Onoda T, Rahman M, Araki A, Juliana FM, Tanaka N and Asao H; WSB-1, a novel IL-21 receptor binding molecule, enhances the maturation of IL-21 receptor. Cell Immunol. 269, 54-59, 2011.
Nara H, Onoda T, Rahman M, Araki A, Juliana FM, Tanaka N and Asao H; Regulation of interleukin-21 receptor expression and its signal transduction by WSB-2. Biochem. Biophys. Res. Commun. 392, 171-177, 2010.
Li J, Nara H, Rahman M, Juliana FM, Araki A and Asao H; Impaired IL-7 signaling may explain a case of atypical JAK3-SCID. Cytokine 49, 221-228, 2010.
Tojo N, Kashiwagi Y, Nishitsuka K, Yamamoto S, Asao H, Sugawara N, Yamashita T, Yamamoto T, and Yamashita H; Interactions between vitreous-derived cells and vascular endothelial cells in vitreoretinal diseases. Acta Ophthalmol. 88, 564-570, 2010.
Mizuguchi M, Asao H, Hara T, Higuchi M, Fijii M and Nakamura M; Transcriptional Activation of the Interleukin-21 Gene and Its Receptor Gene by Human T-cell Leukemia Virus Type 1 Tax in Human T-cells. J. Biol. Chem. 284, 25501-25511, 2009.
Onoda T, Rahman M, Nara H, Araki A, Makabe K, Tsumoto K, Kumagai I, Kudo T, Ishii N, Tanaka N, Sugamura K, Hayasaka K and Asao H; Human CD4+ central and effector memory T cells produce IL-21; Effect on cytokine-driven proliferation of CD4+ T cell subsets. Int. Immunol. 19, 1191-1199, 2007.
Rahman M, Nara H, Onoda T, Araki A, Li J. Hoshino T. and Asao H; Cloning and Characterization of an Isoform of Interleukin-21. FEBS Letters 581, 4001-4009, 2007.
Mizuguchi M, Higuchi M, Fujii M, Asao H and Nakamura M; HTLV-I tax induces IL-21 and IL-21R gene expression. AIDS Res. Hum. Retrov. 23, 626, 2007.
Iuchi Y, Okada F, Onuma K, Onoda T, Asao H, Kobayashi M and Fujii J; Elevated oxidative stress in erythrocytes due to a SOD1 deficiency causes anaemia and triggers autoantibody production. Biochem. J. 402, 19-27, 2007.
Arawaka S, Wada M, Goto S, Karube H, Sakamoto M, Ren CH, Koyama S, Nagasawa H, Kimura H, Kawanami T, Kurita K, Tajima K, Daimon M, Baba M, Kido T, Saino S, Goto K, Asao H, Kitanaka C, Takashita E, Hongo S, Nakamura T, Kayama T, Suzuki Y, Kobayashi K, Katagiri T, Kurokawa K, Kurimura M, Toyoshima I, Niizato K, Tsuchiya K, Iwatsubo T, Muramatsu M, Matsumine H, Kato T.; The role of G-protein-coupled receptor kinase 5 in pathogenesis of sporadic Parkinson's disease. J Neurosci. 26, 9227-9238, 2006.
Kobayashi H, Tanaka N, Asao H, Miura S, Kyuuma M, Semura K, Ishii N, Sugamura K; Hrs, a mammalian master molecule in vesicular transport and protein-sorting, suppresses the degradation of ESCRT proteins STAM1 and STAM2. J Biol Chem. 280, 10468-10477, 2005.
Kitasato Y, Hoshino T, Okamoto M, Kato S, Koda Y, Nagata N, Kinoshita M, Koga H, Yoon DY, Asao H, Ohmoto H, Koga T, Rikimaru T and Aizawa H; Enhanced expression of IL-18 and its receptor in idiopathic pulmonary fibrosis. Am J Respir Cell Mol Biol. 6, 619-625, 2004.
Kanazawa C, Morita E, Yamada M, Ishii N, Miura S, Asao H, Yoshimori T and Sugamura K; Effects of deficiencies of STAMs and Hrs, mammalian class E Vps proteins, on receptor downregulation. Biochem. Biophys. Res. Commun. 309, 848-856, 2003.
Asao H; Mechanism of Interleukin 2-induced Siganal Transduction. Yamagata Med. J. 21, 141-154, 2003.
Kikuchi K, Ishii N, Asao H and Sugamura K; Identification of AMSH-LP containing a Jab1/MPN domain metalloenzyme motif. Biochem. Biophys. Res. Commun. 306, 637-643, 2003.
Morita E, Nakashima A, Asao H, Sato H and Sugamura K; Human parvovirus B19 non-structural protein (NS1) induces cell cycle arrest at G1 phase. J. Virol. 77, 2915-2921, 2003.
Kunzmann S, Wohlfahrt JG, Itoh S, Asao H, Komada M, Akdis CA, Blaser K and Schmidt-Weber CB; SARA and Hgs attenuate susceptibility to TGF-β1-mediated T-cell suppression. FASEB J.17, 194-202, 2003.（before 2002）
Yamada M, Ishii N, Asao H, Murata K, Kanazawa C, Sasaki H and Sugamura K; Signal transducing adaptor molecule STAM1 and STAM2 are required for T-cell development and survival. Mol. Cell. Biol. 22, 8648-8658, 2002.
Katz M, Shtiegman K, Tal-Or P, Yakir L, Mosesson Y, Harari D, Machluf Y, Asao H, Jovin T, Sugamura K, Yarden Y; Ligand-Independent Degradation of Epidermal Growth Factor Receptor Involves Receptor Ubiquitylation and Hgs, an Adaptor Whose Ubiquitin-Interacting Motif Targets Ubiquitylation by Nedd4. Traffic 3, 740-751, 2002.
Ishii N, Owada Y, Yamada M, Miura S, Murata K, Asao H, Kondo H and Sugamura K; Loss of Neurons in the Hippocampus and Cerebral Cortex of AMSH-Deficient Mice. Mol. Cell. Biol. 21, 8626-8637, 2001.
Itoh F, Asao H, Sugamura K, Heldin CH, ten Dijke P and Itoh S; Promoting bone morphogenetic protein signaling through nagative regulation of inhibitory smads. EMBO J. 20, 4132-4142 ,2001.
Kikuchi, K., Kawasaki, Y., Ishii, N., Sasaki, Y., Asao, H., Takeshita, T., Miyoshi, I., Kasai, N. and Sugamura, K.; Suppression of Thymic Development by the Dominant- negative Form of Gads. Int. Immunol., 13, 777-783, 2001.
Asao, H., Okuyama, C., Kumaki, K., Ishii, N., Tsuchiya, S., Foster, D. and Sugamura, K.; The common gamma chain (γc) is an indispensable subunit of the IL-21 receptor complex. J. Immunol., 167, 1-5, 2001.
Morita, E., Tada, K., Chisaka, H., Asao, H., Sato, H., Yaegashi, N. and Sugamura, K.; Human parvovirus B19 induces cell cycle arrest at G2 phase with accumulation of mitotic cyclines. J. Virol., 75, 7555-7563, 2001.
Asao, H. and Fu, X-Y.: Interferon-gamma has dual potentials in inhibiting or promoting cell proliferation. J. Biol. Chem., 275, 867-874, 2000.
Endo, K., Takeshita, T., Kasai, H., Sasaki, Y., Tanaka, N., Asao, H., Kikuchi, K., Yamada, M., Chen, M., O'Shea, J. J. and Sugamura, K. : STAM2, a new member of the STAM femily, binding to the Janus kinases. FEBS Lett., 477, 55-61, 2000.
Miura, S., Takeshita, T., Asao, H., Kimura, Y., Murata, K., Sasaki, Y., Hanai, J., Beppu, H., Tsukazaki, T., Wrana, J. L., Miyazono, K. and Sugamura, K.: Hgs (Hrs), a FYVE domain protein, is involved in Smad signaling through cooperation with SARA. Mol. Cell. Biol., 20, 9346-9355, 2000.
Tanaka, N., Kaneko, K., Asao, H., Kasai, H., Endo, Y., Fujita, T., Takeshita, T. and Sugamura, K.: Possible involvement of a novel STAM- associated molecule "AMSH" in intracellular signal transduction mediated by cytokines. J. Biol. Chem., 274, 19129-19135, 1999.
Takeshita, T., Arita, T., Higuchi, M., Asao, H., Endo, K., Kuroda, H., Tanaka, N., Murata, K., Ishii, N., and Sugamura, K. : STAM, Signal transducing adaptor molecule, is associated with Janus Kinases and involved in signaling for cell growth and c-myc induction. Immunity, 6,449-457, 1997.
Asao, H., Sasaki, Y., Arita, T., Tanaka, N., Endo, K., Kasai, H., Takeshita, T., Endo, Y., Fujita, T. and Sugamura, K : Hrs is associated with STAM, a signal-transducing adaptor molecule. J. Biol. Chem., 272, 32785-32787, 1997.
Higuchi, M., Asao, H., Tanaka, N., Oda, K., Takeshita, T. and Sugamura, K.: Regulation of IL-2 signaling. Leukemia, 11, 416-417, 1997.
Oda, K., Asao, H., Higuchi, M., Tanaka, N., Moffatt, S., Nakamura, M., Tabayashi, K. and Sugamura, K. : Induction of IL-1β-converting enzyme-independent apoptosis by IL-2 in human T cell lines. Int. Immunol., 9, 1303-1310, 1997.
Sugamura, K., Asao, H., Kondo, M., Tanaka, N., Ishii, N., Ohbo, K., Nakamura, M. and Takeshita, T.: The interleukin 2 receptor γ chain: its role in the multiple cytokine receptor complexes and T cell development in XSCID. Annu. Rev. Immunol.,14, 179-205, 1996.
Takeshita, T., Arita, T., Asao, H., Tanaka, N., Higuchi, M., Kuroda, H., Kaneko, K., Munakata, H., Endo, Y., Fujita,T. and Sugamura, K. : Cloning of a Novel Signal-Transducing Adaptor Molecule Containing an Sh3 Domain and ITAM. Biochem. Biophys. Res. Commun., 225, 1035-1039, 1996.
Ohbo, K., Asao, H., Kouro, T., Nakamura, M., Takaki, S., Kikuchi, Y., Hirokawa, K., Tominaga, A., Takatsu, K. and Sugamura, K.: Demonstration of a cross-talk between IL-2 and IL-5 in phosphorylation of IL-2 and IL-5 receptor β chains. Int. Immunol., 8, 951-960, 1996.
Higuchi, M., Asao, H., Tanaka, N., Oda, K., Takeshita, T., Nakamura, M., Van Snick, J. and Sugamura, K.: Dispensability of Jak1 tyrosine kinase for interleukin-2-induced cell growth signaling in a human T cell line. Eur. J. Immunol., 26, 1322-1327, 1996.
Sugamura, K., Asao, H., Kondo, M., Tanaka, N., Ishii, N., Nakamura, M. and Takeshita, T.: The common γ chain for multiple cytokine receptors. Adv. Immunol., 59, 225-277, 1995.
Asao, H., Tanaka, N., Ishii, N., Higuchi, M., Takeshita, T., Nakamura, M., Shirasawa, T. and Sugamura, K. : Interleukin 2-induced activation of JAK3: possible involvement in signal transduction for c-myc induction and cell proliferation. FEBS Letters, 351, 201-206, 1994.
Ishii, N., Asao, H., Kimura, Y., Takeshita, T., Nakamaura, M., Tsuchiya, S., Konno, T., Maeda, M., Uchiyama, T. and Sugamura, K.: Impairment of ligand binding and growth signaling of mutant IL-2 receptor γ chains in patients with X-linked severe combined immunodeficiency. J. Immunol., 153, 1310-1317, 1994.
Tanaka, N., Asao, H., Ohbo, K., Ishii, N., Takeshita, T., Nakamaura, M. and Sugamura, K.: Physical association of JAK1 and JAK2 tyrosine kinases with the interleukin 2 receptor β and γ chains. Proc. Natl. Acad. Sci. USA., 91, 7271-7275, 1994.
Nakamura, M., Asao, H., Takeshita, T. and Sugamura, K.: Interleukin-2 receptor heterotrimer complex and intracellular signaling. Seminars in Immunology, 5, 309-317, 1993.
Kumaki, S., Kondo, M., Takeshita, T., Asao, H., Nakamura, M. and Sugamura, K.: Cloning of the mouse interleukin 2 receptor γ chain: Demonstration of functional differences between the mouse and human receptors. Biochem. Biophys. Res. Commun, 193, 356-363, 1993.
Asao, H., Takeshita, T., Ishii, N., Kumaki, S., Nakamura, M., and Sugamura, K.: Reconstitution of the functional IL-2 receptor complexes on fibroblastoid cells: Involvement of the cytoplasmic domain of the γ chain in two distinct signaling pathways. Proc. Natl. Acad. Sci. USA. , 90, 4127-4131, 1993.
Takeshita, T., Asao, H., Ohtani, K., Ishii N., Kumaki, S., Tanaka, N., Munakata, H., Nakamura, M. and Sugamura, K.: Cloning of the γ chain of the human IL-2 receptor. Science, 257, 379-382, 1992.
Asao, H., Kumaki, S., Takeshita, T., Nakamura, M. and Sugamura, K.: IL-2-dependent in vivo and in vitro tyrosine phosphorylation of IL-2 receptor γ chain. FEBS Letters, 304, 141-145, 1992.
Takeshita, T., Ohtani, K., Asao, H., Kumaki, S., Nakamura, M. and Sugamura, K.: An associated molecule, p64, with IL-2 receptor β chain: its possible involvement in formation of the functional IL-2 receptor complex. J. Immunol., 148, 2154-2158, 1992.
Ohbo, K., Takeshita, T., Asao, H., Kurahayashi, Y., Tada, K., Mori, H., Hatakeyama, M., Taniguchi, T. and Sugamura, K.: Monoclonal antibodies defining distinct epitopes of the human IL-2 receptor β chain and their differential effects on IL-2 responses. J. Immunol. Methods, 142, 61-72, 1991.
Sugamura, K., Asao, H., Suzuki, J. and Takeshita, T.: Identification of a third component, γ chain (p64), of interleukin 2 receptor. In " Cytokines: Basic principles and clinical applications", Romagnani, S. and Abbas, A.K. eds., Raven Press, New York, pp145-146, 1990.
Takeshita, T., Asao, H., Suzuki, J. and Sugamura, K.: An associated molecule, p64, with high-affinity interleukin 2 receptor. Int. Immunol., 2, 477-480, 1990.
Asao, H., Takeshita, T., Nakamura, M., Nagata, K. and Sugamura, K.: The evidence for the IL-2 receptor β chain processing from p70 to p75. Int. Immunol., 2, 470-472, 1990.
Asao, H., Takeshita, T., Nagata, K., Nakamura, M. and Sugamura, K.: Interleukin 2 (IL-2)-induced tyrosine phosphorylation of IL-2 receptor p75. J. Exp. Med., 171, 637-644, 1990.
Suzuki, J., Takeshita, T., Ohbo, K., Asao, H., Tada, K. and Sugamura, K.: IL-2 receptor subunit, p75: direct demonstration of its IL-2 binding ability by using a novel monoclonal antibody. Int. Immunol., 1, 373-377, 1989.
Takeshita, T., Goto, Y., Tada, K., Nagata, K., Asao, H. and Sugamura, K.: Monoclonal antibody defining a molecule possibly identical to the p75 subunit of interleukin 2 receptor. J. Exp. Med., 169, 1323-1332, 1989.